Leptin, the protein product of the obese gene, promotes weight lose by decreasing appetite and increasing thermogenesis. The majority of obese humans have high leptin levels suggesting resistance to, or deficient activity of, leptin. Cardiovascular morbidity and mortality is increased in obesity. Obese humans also have high incidence of obstructive sleep apnea, a disorder that itself increases cardiovascular risk. Chemoreflex abnormalities may predispose obese persons to sleep apnea. Preliminary data from our studies in animals and humans provide exciting evidence, first, that the central chemoreflexes are impaired in human obesity, and second, that exogenous leptin increases central chemoreflex sensitivity in normal mice. While the metabolic effects of leptin have received great attention, little is known about the interactions between leptin and the cardiovascular system. Using state-of-the-art methods for investigating neural circulatory control in humans, this study tests the following hypotheses: 1) that central chemoreflex sensitivity and arterial baroreflex sensitivity are impaired in obese humans and that this impairment is secondary to deficient action of leptin; 2) that baroreflex and chemoreflex impairment in obesity occur independent of body fat content, and are present even after weight loss and in lean offspring of obese parents; 3) that impairment in these reflexes is not explained by either obstructive sleep apnea or high levels of insulin; and 4) that deficient leptin action contributes primarily to abdominal and not hip obesity. In human obesity, leptin levels are linked to body fat content, but are variable for any given level of body fat. Thus mechanisms other than adiposity alone modulate leptin expression. Norepinephrine, activating via the beta-3 receptor, down regulates leptin production. We will therefore test in humans the additional hypothesis that acute and chronic sympathetic activation, acting via the beta-3 receptor, decrease leptin expression. Thus, studies of the influence of leptin on neuronal circulatory control will be complemented by studies examining the effect of neural mechanisms on leptin expression. These studies may have important and novel implication for our understanding of the relationship between obesity and both obstructive sleep apnea and cardiovascular disease.